Ethers of 1-(2-propynyloxy)-2-amino-3-propanol

ABSTRACT

The invention is dealing with compounds of the formula: ##STR1## and pharmaceutically acceptable salts thereof, in which R 1  and R 2  each represent a lower alkyl radical or a phenyl radical, or, together with the carbon atom to which they are bound, a cycloalkyl radical having at the most 7 carbon atoms; R 3  represents hydrogen, a lower alkyl radical, or the phenyl radical; R 4  and R 5  each represent a lower alkyl radical, or, together with the nitrogen atom to which they are bound, a heterocyclic amino radical such as the pyrrolidinyl or morpholino radicals; and R 6  represents a lower alkyl radical, a phenyl radical, a benzyl radical, or the 1-ethynyl-cyclohexyl radical, which compounds can be used in the treatment of angina pectoris.

The present invention is referring to new ethers of1-(2-propynyloxy)-2-amino-3-propanol, to processes for their preparationand to a pharmaceutical preparation containing said ethers as the activeprinciple.

More particularly the present invention is dealing with compounds of thegeneral formula: ##STR2## in which R₁ and R₂ each represent,independently of one another, a lower alkyl radical or a phenyl radical,or, together with the carbon atom to which they are bound, a cycloalkylradical having at the most 7 carbon atoms; R₃ represents hydrogen, alower alkyl radical or the phenyl radical; R₄ and R₅ being identical ordifferent each represent a lower alkyl radical, or, together with thenitrogen atom to which they are bound, a heterocyclic amino radical,such as the pyrrolidinyl and morpholino radicals; R₆ represents a loweralkyl radical, a phenyl radical, a benzyl radical or the1-ethynyl-cyclohexyl radical, as well as the pharmaceutically acceptablesalts of these compounds.

The invention is further dealing with a process of obtaining thecompounds I from a suitably substituted ether of 2-chloro-3-aminopropanol and an acetylenic alcohol, preferably by phase-transfercatalysis.

The invention also concerns the use of the compounds I or theirpharmaceutically acceptable salts in the treatment of cardiacdisturbances, especially in humans.

There are already numerous known aryloxyamino propanols deriving fromthe structure of 1-isopropylamino-3-(1-napthyloxy)-2-propanol(propanolol), a compound known for its β-blocking properties. Themodifications made to this structure concern either the naphthyl radical(by substitution and/or introduction of an other unsaturated group, orthe aminopropanol chain itself (by etherification and/or isomerisation).

In certain cases, the compounds obtained retain the β-blocking activity;this is the case for example with2,3-cis-1,2,3,4-tetrahydro-5-(2-hydroxy-3-tert.butyl-aminopropoxy)-2,3-naphthalenediol(DE No. 2.258.995).

In other cases, the expected β-blocking activity cannot be demonstratedand the compounds are active on the central nervous system; this occursfor example with 2-isopropylamino-3-(1-naphthyloxy)-1-propanol, aposition isomer of propanolol [J.Med.Chem. 13, 398 (1970)]. Compoundswhose general structure corresponds to ethers of the previouslymentioned compound also have no β-blocking properties, but are active onthe central nervous system (U.S. Pat. No. 4,060,613).

In contrast, it has now been discovered that compounds whose generalstructure can be considered to resemble that of the compounds describedin U.S. Pat. No. 4,060,613, but in which the aminopropane chain is nolonger substituted by an aryloxy radical, have interesting β-blockingproperties.

These compounds, having the general formula (I), are prepared inaccordance with the following reaction scheme preferably by means ofphase-transfer catalysis: ##STR3## Hal means halogen and preferablychlorine. It should be noted that this reaction, which is brought aboutthrough an immonium ion, leads to a rearrangement of the aminofunction--NR₄ R₅.

The halogenated derivative used in this synthesis is prepared accordingto known means indicated, for example, in U.S. Pat. No. 3,663,566.

The preferred reaction is effected by adding small quantities of thehalogenated derivative to a solution constituted of a suitableacetylenic alcohol, an equivalent quantity or small excess of a base,preferably sodium-hydroxide, and a phase-transfer catalyst, such asbenzyltriethylammoniumchloride.

If necessitated by the excessive viscosity of the reaction medium, asolvent, such as benzene or methylene chloride, is added beforerefluxing. The compound obtained is then extracted in the usual manner,e.g. with the aid of ether.

According to a variant of this process, the halogenated derivative canbe replaced by the corresponding sulfonate, prepared by the usual meansfrom the amino-alcohol N(R₄ R₅)--CH₂ --CH(OH)--CH₂ OR₆ and asulfonylhalide, such as mesylchloride or tosylchloride. This variant isto be used in preference when the substituent R₆ has functions which areliable to be degraded by the halogenation agents used to obtain thehalogenated derivative.

The cardiovascular activity of the compounds of the invention wasdemonstrated in the dog, according to the following procedure.

The animal was anaesthetised with chloralose and record was kept of:

the arterial frequency at a femoral artery via a probe connected to aBELLET AND HOWEL pressure cell,

the amplitude of cardiac contractions (Contractile force) by means of astrain gauge fixed by four suture points on the left ventricularepicardium on the great axis of the organ, after thoracotomy at the 5thlefthand intercostal space.

The β sympathetic reactivity was also tested by recording the inhibitionof tachycardia induced by an injection of isoprenaline (0.5 g kg⁻¹ I.V.)before administration of the tested product, and then 5 minutes afterthis administration, and then every 15 minutes.

Table A hereinafter consolidates the measurements carried out on thesedifferent parameters, the results being expressed as percentage ofmaximum variation with respect to the values before treatment. All thecompounds of the invention were administered in doses of 5 mg kg⁻¹ I.V.,with the exception of compound no. 3 which was administered in doses of1 mg kg⁻¹ I.V.

                  TABLE A                                                         ______________________________________                                        Compound                                                                              Cardiac   Arterial  Contractile                                                                           Tachycardia                               no.*    frequency pressure  force   inhibition                                ______________________________________                                        1       -15%      -28,3%    +28%    -58,7%                                    2       -28%      -36%      -45%    -18%                                      3       -44%      -38%      -50%    -62%                                      4       -19%      0         -11%    -23%                                      6       -17,7%    -18,2%    +70,2%  -62,2%                                    7       -19,7%    -15,7%    +34,7%  -59,7%                                    8       -11,5%    -25%      +53,3%  -53,5%                                    9       +18,3%    -34,2%    -11,5%  -30,8%                                    11      -20%      -18,6%    -14,5%  -18,8%                                    13      -10,7%    -16,6%    -15,3%  -34,3%                                    14      -19,5%    +18,6%    +14%    -41,9%                                    ______________________________________                                         *The chemical structure of the compounds are shown in table B, page 11.  

These products were also shown to have a reduced toxicity, for examplethe compounds 6 and 7 possess an oral LD₅₀ value in mice greater than600 mg/kg.

This set of properties allows the compounds according to the inventionto be recommended as cardiovascular-medicaments especially for thetreatment of angina pectoris.

The compounds of the invention may be administered enterally orparenterally, preferably in a daily dose from 1 to 10 mg per kgbodyweight. The preferred doses in human beings may vary between 100 and600 mg per day.

Mixed with suitable auxiliaries the compounds I may be compressed intosolid dosage units such as pills, tablets, coated tablets or beprocessed into capsules. By means of suitable liquids the compounds mayalso be applied as an injection or oral preparation in the form ofsolutions, suspensions or emulsions.

By a lower alkyl group in the definition of R₁, R₂, R₃, R₄, R₅ and R₆ isto be understood an alkyl group with 1 to 6 carbon atoms, such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl,hexyl.

The cycloalkyl radical in the definition of R₁ and R₂ is preferably acyclohexyl or cycloheptyl radical.

By the heterocyclic amino radical as used in the definition of R₄ and R₅is meant a 5- or 6-membered nitrogen containing ring which optionallymay possess one additional hetero-atom, such as a pyrrolidinyl ormorpholino radical. The pyrrolidinyl radical is the preferred radical.

With respect to the definition of R₁ and R₂ preference is given to theradicals methyl, phenyl or cyclohexyl.

The preferred R₃ radical is hydrogen, methyl or phenyl.

The radical which is most preferred in the definition of R₆ is theisobutyl radical.

Preferred compounds according to the invention are the compounds 1 and 6of Table B.

The compounds of formula I possess a chiral carbon in case R₁ and R₂ aredifferent radicals. In such case both the racemic mixture I as well asthe separate optical enantiomers belong to the compounds of theinvention. The said optical enantiomers can be prepared in the usualmanner by resolution of the racemic mixture or directly using opticallyactive starting products.

EXAMPLE 11-[1-(1-propynyl)-cyclohexyloxy]-2-(N-pyrrolidinyl)-3-iso-butoxypropane

33 g of 1-pyrrolidinyl-2-chloro-3-isobutoxypropane were graduallyintroduced into a reactor containing 41.4 g of 1-propynyl cyclohexanol,30 g of sodium-hydroxide previously dissolved in 30 ml of water and 3.1g of benzyl triethylammonium chloride, while stirring well. When theaddition had ended, the mixture was refluxed for 4 hours while thestirring was maintained. After cooling, the product formed was extractedwith ether. The ether phase was filtered, decanted and washed withwater, dried over sodium sulphate and then evaporated. Afterdistillation of the residue 22 g of the product of the heading wereobtained in the form of a clear yellow liquid. BP₀,5 =130°-135° C.,n_(D) ²⁰ =1,483.

EXAMPLE 21-(1-methyl-1-phenyl-2-propynyloxy)-2-(N-pyrrolidinyl)-3-isobutoxypropane

In a corresponding manner as described in the previous example 6 g ofthe liquid product of the heading were obtained by refluxing for 5 hoursa mixture constituted by 14.6 g of 2-phenyl-3-butyne-2-ol, 10 g ofsodium hydroxide in 10 ml of water, 1,1 g of benzyl triethylammoniumchloride and 11 g of 1-pyrrolidinyl-2-chloro-3-isobutoxy propane. BP₀,5=143°-145° C.; n_(D) ²⁰ =1.502.

The liquid base thus obtained was converted into the hydrochloride salt.Melting point HCl salt: 154° C. Elemental analysis:

    ______________________________________                                                 C %         H %    N %                                               ______________________________________                                        Theoretical                                                                              68.92         8.81   3.83                                          Found      67.62         8.63   3.79                                          ______________________________________                                    

EXAMPLE 31-(1-methyl-1-phenyl-2-propynyloxy)-2-(N-pyrrolidinyl)-3-phenoxy propane

27.5 g of 1-pyrrolidinyl-2-chloro-3-phenoxy propane were graduallyintroduced into a reactor containing 29.2 g of 2-phenyl-3-butyne-2-ol,20 g of sodium hydroxide in 20 ml of water and 2.27 g of benzyltriethylammonium, while stirring well. When the addition ended, thereaction medium was very thick and 20 ml of benzene were added beforerefluxing for 5 hours. The product was then extracted with ether,filtered, washed and dried as indicated in Example 1.

After distillation, 21 g of the product of the heading were collectedhaving a boiling point: BP₀,5 =190° C. and e refractive index n_(D) ²⁰=1.550.

EXAMPLE 41-(1-methyl-1-phenyl-2-propynyloxy)-2-(N-pyrrolidinyl)-3-(1-ethynylcyclohexyloxy)-propane

Initially, the mesylate was prepared by adding, drop by drop, 23 ml ofmesyl chloride to 56 g of 1-(1-ethynyl cyclohexyloxy)-3-(N-pyrrolidinyl)propane-2-ol in 135 ml of pyridine, the temperature of the reactionmedium being kept between 0° C. and -5° C. When the reaction had ended,the mesylate formed was extracted with chloroform, and then with ether.

After purification and elimination of the ether, the starting productobtained was used in the following reactionstep.

16 g of mesylate of 1-(1-ethynyl cyclohexyloxy)-3-(N-pyrrolidinyl)propane-2-ol were added drop by drop at ambient temperature to a reactorcontaining 10 g of 2-phenyl-3-butyne-2-ol, 10 g of sodium hydroxide in10 ml of water and 1.1 g of benzyl triethylammonium chloride. When theaddition was finished, the reaction medium was fairly thick; refluxingwas then carried out gently, while stirring moderately. Refluxing wasmaintained for about 14 hours and then, after cooling, the product ofthe heading was extracted with ether, as indicated in Example 1. Afterdistillation, 24 g of product were collected having a refractive indexn_(D) ²⁰ =1.523.

EXAMPLE 5

Compounds whose characteristics are summarized in Table B hereinafterwere also prepared in accordance with the process described in Example4:

                                      TABLE B                                     __________________________________________________________________________                                                         F °C. (salt)                                                           or                       Compound no.                                                                          R.sub.1      R.sub.2   R.sub.3                                                                            NR.sub.4 R.sub.5                                                                     R.sub.6   n.sub.D.sup.20           __________________________________________________________________________                                                         (base)                    1 see also (Example 2)                                                                ##STR4##    CH.sub.3  H                                                                                   ##STR5##                                                                            CH.sub.2CH(CH.sub.3).sub.2                                                              F.sub.HCl                                                                     = 154° C.          2                                                                                     ##STR6##    CH.sub.3  H    N(C.sub.2 H.sub.5).sub.2                                                              ##STR7## n.sub.D.sup.20 =                                                              1,526                     3 see also (Example 3)                                                                ##STR8##    CH.sub.3  H                                                                                   ##STR9##                                                                             ##STR10##                                                                              n.sub.D.sup.20 =                                                              1,550                     4                                                                                     ##STR11##   CH.sub.3  H                                                                                   ##STR12##                                                                           C.sub.2 H.sub.5                                                                         n.sub.D.sup.20 =                                                              1,510                     5 compound of (Example 4)                                                             ##STR13##   CH.sub.3  H                                                                                   ##STR14##                                                                            ##STR15##                                                                              n.sub.D.sup.20 =                                                              1,523                     6 see also (Example 1)                                                                ##STR16##             CH.sub.3                                                                            ##STR17##                                                                           CH.sub.2CH(CH.sub.3).sub.2                                                              n.sub.D.sup.20 =                                                              1,483                     7                                                                                     ##STR18##             H                                                                                   ##STR19##                                                                           CH.sub.2CH(CH.sub.3).sub.2                                                              n.sub.D.sup.20 =                                                              1,480                     8                                                                                     ##STR20##             H                                                                                   ##STR21##                                                                           (CH.sub.2).sub.3CH.sub.3                                                                n.sub.D.sup.20 =                                                              1,483                     9                                                                                     ##STR22##                                                                                            ##STR23##                                                                          ##STR24##                                                                           CH.sub.2CH(CH.sub.3).sub.2                                                              n.sub.D.sup.20 =                                                              1,524                    10                                                                                     ##STR25##   CH.sub.3                                                                                 ##STR26##                                                                          ##STR27##                                                                           CH.sub.2CH(CH.sub.3).sub.2                                                              n.sub.D.sup.20 =                                                              1,525                    11                                                                                     ##STR28##             H                                                                                   ##STR29##                                                                           CH.sub.2CH(CH.sub.3).sub.2                                                              n.sub.D.sup.20 =                                                              1,481                    12      C.sub.2 H.sub.5                                                                            (CH.sub.2).sub.3CH.sub.3                                                                 ##STR30##                                                                          ##STR31##                                                                           CH.sub.2CH(CH.sub.3).sub.2                                                              n.sub.D.sup.20 =                                                              1,493                    13      CH.sub.3     CH.sub.2CH(CH.sub.3).sub.2                                                              H                                                                                   ##STR32##                                                                           CH.sub.2CH(CH.sub.3).sub.2                                                              n.sub.D.sup.20 =                                                              1,459                    14      CH.sub.3     CH.sub.3  H                                                                                   ##STR33##                                                                           CH.sub.2CH(CH.sub.3).sub.2                                                              F.sub.fumarate =                                                              135° C.           __________________________________________________________________________

We claim:
 1. A compound of the formula: ##STR34## or a pharmaceuticallyacceptable salt thereof, in which R₁ and R₂ each represent,independently of one another, a C₁ -C₆ alkyl radical or a phenylradical, or, together with the carbon atom to which they are attached,form a cycloalkyl radical having at the most 7 carbon atoms; R₃represents hydrogen, a C₁ -C₆ alkyl radical or the phenyl radical; R₄and R₅, together with the nitrogen atom to which they are attached, forma pyrrolidinyl or morphilino radical, and R₆ represents a C₁ -C₆ alkylradical, a phenyl radical, a benzyl radical, or the 1-ethynylcyclohexylradical.
 2. Compound according to claim 1, in which R₁ is methyl, R₂ isphenyl, R₃ is hydrogen, R₆ is isobutyl and the group NR₄ R₅ is thepyrrolidinyl radical.
 3. Compound according to claim 1, in which R₁ andR₂ together with the carbon atom to which they are bound represent thecyclohexyl radical, R₃ is methyl, R₆ is isobutyl and the group NR₄ R₅represents the pyrrolidinyl radical.
 4. Compound according to claim 1,in which R₁ is phenyl, R₂ is methyl, R₃ is hydrogen, R₆ is ethyl and thegroup NR₄ R₅ is the morpholino radical.
 5. Pharmaceutical compositionuseful in the treatment of angina pictoris comprising an effectiveamount of at least one compound in accordance with any one of claims 1,2, 3 or 4, in association with appropriate pharmaceutical excipients. 6.A method of treating patients with angina pectoris wherein a compoundaccording to any one of claims 1, 2, 3 or 4 is administered to saidpatients at daily doses of between 100 and 600 mg.